Mechanisms leading to disseminated apoptosis following NMDA receptor blockade in the developing rat brain
Mechanisms leading to disseminated apoptosis following NMDA receptor blockade in the developing rat brain
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DOI：
10.1016/j.nbd.2004.03.013
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发表时间：
2004-07-01
影响因子：
6.1
通讯作者：
Ikonomidou, C
中科院分区：
文献类型：
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作者：
Hansen, HH;Briem, T;Ikonomidou, C
正在发育的啮齿动物大脑很容易受到 N-甲基-D-天冬氨酸 (NMDA) 受体的药物阻断，这可能导致严重的播散性细胞凋亡性神经变性。在这里，我们发现，对 7 日龄大鼠全身施用 NMDA 受体拮抗剂 MK801 会导致细胞外信号调节激酶 1/2 (ERK1/2) 的活性受损，并降低显示严重凋亡性神经变性的大脑区域中磷酸化 cAMP 反应元件结合蛋白 (CREB) 的水平。 ERK1/2 和 CREB 活性受损与神经营养蛋白表达的持续耗竭同时发生，特别是脑源性神经营养因子 (BDNF)。补充 BDNF 完全可以防止 MK801 诱导的未成熟神经元培养物中的神经毒性，并且 Ras 的转基因组成型激活与针对 MK801 诱导的细胞凋亡性神经元死亡的显着保护相关。这些数据表明，体内 NMDA 受体与 ERK1/2-CREB 信号通路的解偶联会导致发育中的啮齿动物大脑中神经元的大量凋亡缺失。 (C) 2004 Elsevier Inc. 保留所有权利。
The developing rodent brain is vulnerable to pharmacological blockade of N-methyl-D-aspartate (NMDA) receptors which can lead to severe and disseminated apoptotic neurodegeneration. Here, we show that systemic administration of the NMDA receptor antagonist MK801 to 7-day-old rats leads to impaired activity of extracellular signal-regulated kinase 1/2 (ERK1/2) and reduces levels of phosphorylated cAMP-responsive element binding protein (CREB) in brain regions which display severe apoptotic neurodegeneration. Impaired ERK1/2 and CREB activity were temporally paralleled by sustained depletion of neurotrophin expression, particularly brain-derived neurotrophic factor (BDNF). BDNF supplementation fully prevented MK801-induced neurotoxicity in immature neuronal cultures and transgenic constitutive activation of Ras was associated with marked protection against MK801-induced apoptotic neuronal death. These data indicate that uncoupling of NMDA receptors from the ERK1/2-CREB signaling pathway in vivo results in massive apoptotic deletion of neurons in the developing rodent brain. (C) 2004 Elsevier Inc. All rights reserved.